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EP2929323B1 - Sondes particulaires sensibles à un analyte ciblé pouvant être individuellement déployées de manière flexible et procédé de fabrication et d'utilisation - Google Patents

Sondes particulaires sensibles à un analyte ciblé pouvant être individuellement déployées de manière flexible et procédé de fabrication et d'utilisation Download PDF

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Publication number
EP2929323B1
EP2929323B1 EP12822973.9A EP12822973A EP2929323B1 EP 2929323 B1 EP2929323 B1 EP 2929323B1 EP 12822973 A EP12822973 A EP 12822973A EP 2929323 B1 EP2929323 B1 EP 2929323B1
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Prior art keywords
target
analyte
probes
sensitive
probe
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German (de)
English (en)
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EP2929323A1 (fr
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Dmitri Boris Papkovsky
James Niall HYNES
Richard Fernandes
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Agilent Technologies Inc
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Agilent Technologies Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6408—Fluorescence; Phosphorescence with measurement of decay time, time resolved fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6432—Quenching
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/061—Sources
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/12—Circuits of general importance; Signal processing

Definitions

  • Optically-active, target-analyte sensitive indicator dyes and compounded materials containing such dyes are widely used in the construction of probes and sensors for quantification and monitoring of target-analytes.
  • Such sensors are particularly suited for use in those situations where nondestructive and/or continuous quantification and/or monitoring of a target-analyte within an enclosed space is necessary or desired as such sensors are amenable to repetitive, non-invasive and contactless interrogation through a variety of common barrier materials.
  • Sensors employing an optically-active, target-analyte sensitive indicator dye commonly immobilize the dye by embedding the dye within a polymer matrix that is permeable to the target-analyte, hereinafter referenced as an optically-active indicator matrix.
  • the optically-active indicator matrix is commonly deposited as a solid-state coating, film, layer or dot on an appropriate substrate support material to form autonomously deployable sensors. See for example United States Published Patent Applications 2011/0136247 , 2009/0029402 , 2008/199360 , 2008/190172 , 2007/0042412 , and 2004/0033575 ; United States Patents 8,242,162 , 8,158,438 , 7,862,770 , 7,849,729 , 7,749,768 , 7,679,745 , 7,674,626 , 7,569,395 , 7,534,615 , 7,368,153 , 7,138,270 , 6,989,246 , 6,689,438 , 6,395,506 , 6,379,969 , 6,080,574 , 5,885,843 , 5,863,460 , 5,718,842 , 5,595,708 ,
  • assay vessels and packaging films with an integrated optically-active indicator sensor Due to a prolific increase in the use of such optical sensors, manufacturers have begun to supply assay vessels and packaging films with an integrated optically-active indicator sensor, thereby facilitating use of such sensors by the end user, particularly those who assay large numbers of test samples on a regular basis.
  • Examples of commercially available assay vessels with an integrated optically-active sensor include microtitter plates available from BD Biosciences of Franklin Lakes, New Jersey, USA and PreSens - Precision Sensing GmbH of Regensberg, Germany; disposable plastic vials available from Mocon of Minneapolis, Minnesota, USA and Luxcel Biosciences, Ltd. of Cork, Ireland, and culturing flasks available from PreSense.
  • optically active sensors are usually integrated into assay vessels by depositing a solution or suspension of the optically-active indicator matrix directly onto an inner surface of the assay vessel as a polymeric 'cocktail', or adhesively attaching a solid state sensor to an inner surface of the assay vessel.
  • sensor-integrated assay vessels restricts the end user to use of only those types of assay vessels available with an integrated sensor, thereby reducing the ability to change or adjust experimental conditions in terms of the assay vessel type, size, geometry, alignment, material of construction, etc. Due to high start-up production costs, and strong but limited demand for all but a few types of "sensorized” assay vessels, the industry is unlikely to significantly expand the types of assay vessels available with an integrated sensor.
  • One alternative for avoiding the drawbacks associated with the deployment of solid-state optically active sensors is to employ fluid compositions containing the indicator dye in solution or suspension as a liquid or in the form of solid state nano or micro particles which are added to and blended into the samples being tested. This allows the sensor material to be supplied separately from the assay vessels, thereby facilitating a more versatile use relative to the integrated solid state sensors. However, such sensors contaminate the sample and require the use of a much greater quantity of indicator dye as the dye is diluted by the sample.
  • a first aspect of the invention is a flexibly deployable, discrete target-analyte sensitive probe adapted to be individually and discretely dispensed comprising a porous scaffold particle coated with an optically-active, target-analyte sensitive material, wherein the scaffold particle is a bead and has at least one of (i) a volume of 0.5 to 500 mm 3 , and (ii) a largest dimension of 2 to 20 mm.
  • the probe has a density of greater than 1.2 g/cm 3 so that the probe, when introduced into an assay vessel will remain at or sink to the bottom of the vessel when combined with common test samples.
  • a second aspect of the invention is an article of commerce comprising a plurality of probes in accordance with the first aspect of the invention retained as a commingled supply of probes within a container from which the probes may be individually and discretely dispensed and used.
  • the probes are microbially sanitized probes.
  • a third aspect of the invention is a method for measuring concentration of a target-analyte within an enclosed space employing a probe according to the first aspect of the invention.
  • the method includes the steps of (A) obtaining a supply of the target-analyte sensitive probes according to the first aspect of the invention, (B) placing a known number of probes from the supply of probes within a space to form a sensor comprised of at least one probe, (C) enclosing the space, and (D) ascertaining target-analyte concentration within the enclosed space by: (i) exposing the sensor to excitation radiation to create an excited sensor, (ii) measuring radiation emitted by the excited sensor, and (iii) converting the measured emission to a target-analyte concentration based upon a known conversion algorithm.
  • a fourth aspect of the invention is a method for measuring concentration of a target-analyte within the chamber of a plurality of receptacles employing probes dispensed from the second aspect of the invention.
  • the method includes the steps of (A) obtaining an article of commerce according to the second aspect of the invention, (B) dispensing a first known number of probes from the container, constituting a first fraction of the total number of commingled probes, into a chamber defined by a first receptacle to form a first sensor comprised of at least one probe, (C) dispensing a second known number of probes from the same container, constituting a second fraction of the total number of commingled probes, into the chamber of a second receptacle to form a second sensor comprised of at least one probe, wherein the second receptacle is different than and dissimilar to the first receptacle, (D) enclosing the chamber defined by the first receptacle, (
  • a fifth aspect of the invention is a method for monitoring changes in target-analyte concentration within an enclosed space employing a target-analyte sensitive probe according to the first aspect of the invention.
  • the method includes the steps of (A) obtaining a supply of the target-analyte sensitive probes according to the first aspect of the invention, (B) placing a known number of probes from the supply of probes within a space to form a sensor comprised of at least one probe, (C) enclosing the space, (D) ascertaining target-analyte concentration within the enclosed space over time by: (i) taking at least two emission measurements over time, each measurement comprising the steps of: (1) exposing the sensor to excitation radiation to create an excited sensor, and (2) measuring radiation emitted by the excited sensor, (ii) measuring passage of time between at least two of the emission measurements to determine a time interval between identified emission measurement, and (iii) converting at least the identified emission measurements to a target-analyte concentration based upon
  • a sixth aspect of the invention is a method for measuring concentration of a target-analyte of interest within an enclosed space employing different target-analyte sensitive probes according to the first aspect of the invention, wherein the target-analyte of interest is selectable from and selectively transitional amongst a plurality of different target-analytes without accessing the space once enclosed.
  • the method includes the steps of (A) obtaining a supply of the target-analyte sensitive probes according to the first aspect of the invention wherein the supply includes probes that are sensitive to different target-analytes and uniquely interrogatable relative to one another, (B) placing at least two of the obtained probes sensitive to different target-analytes within a space, to form a sensor sensitive to at least two different target-analytes, (C) enclosing the space, and (D) ascertaining concentration of a target-analyte of interest within the enclosed space, selected from the at least two different target-analytes to which the at least two placed probes are sensitive, by: (i) exposing the sensor to excitation radiation effective for exciting the probe sensitive to the target-analyte of interest, (ii) measuring radiation emitted by the excited probe sensitive to the target-analyte of interest, and (iii) converting the measured emission to a concentration of the target-analyte of interest based upon
  • a seventh aspect of the invention is method for measuring concentration of at least two different target-analytes within an enclosed space employing different target-analyte sensitive probes according to the first aspect of the invention.
  • the method includes the steps of (A) obtaining a first supply of target-analyte sensitive probes according to the first aspect of the invention which are sensitive to a first target-analyte, (B) obtaining a second supply of target-analyte sensitive probes according to the first aspect of the invention which are sensitive to a second target-analyte which is different from the first target-analyte, and wherein the probes sensitive to a first target-analyte and the probes sensitive to a second target-analyte are uniquely interrogatable relative to one another, (C) placing at least one probe from the first supply of probes and at least one probe from the second supply of probes within a space, to form a sensor sensitive to both first and second target-analytes, (D)
  • An eighth aspect of the invention is method for monitoring changes in concentration of at least two different target-analytes within an enclosed space employing different target-analyte sensitive probes according to the first aspect of the invention.
  • the method includes the steps of (A) obtaining a first supply of target-analyte sensitive probes according to the first aspect of the invention which are sensitive to a first target-analyte, (B) obtaining a second supply of target-analyte sensitive probes according to the first aspect of the invention which are sensitive to a second target-analyte which is different from the first target-analyte, and wherein the probes sensitive to a first target-analyte and the probes sensitive to a second target-analyte are uniquely interrogatable relative to one another, (C) placing at least one probe from the first supply of probes and at least one probe from the second supply of probes within a space, to form a sensor sensitive to both first and second target-analytes, (D
  • a method of manufacturing a probe includes the steps of (A) preparing a coating cocktail which contains at least the optically-active target-analyte sensitive material dissolved in a solvent, (B) applying the cocktail to the porous scaffold particle, and (C) allowing the applied cocktail to dry, whereby a solid-state thin film coating of optically-active target-analyte sensitive material is formed on the scaffold particle to form the probe.
  • the scaffold particle of the probe of the invention has a volume of 5 to 100 mm 3 .
  • the scaffold particle of the probe of the invention has a largest dimension of 3 to 10 mm.
  • the scaffold particle material of the probe of the invention is porous glass.
  • the scaffold particle of the probe of the invention is translucent to interrogation light.
  • the target-analyte sensitive material of the probe of the invention is a photoluminescent material, wherein the. the photoluminescent material includes at least a fluorescent or phosphorescent indicator dye having a responsive optical characteristic that changes in response to changes in the concentration or partial pressure of target-analyte to which the dye is exposed.
  • the responsive optical characteristic is at least one of photoluminescence lifetime and photoluminescence intensity
  • the indicator dye is sensitive to the partial pressure of oxygen
  • the coating comprises a target-analyte sensitive indicator dye incorporated in a target-analyte permeable polymeric matrix, wherein the target-analyte sensitive indicator dye is an oxygen sensitive photoluminescent transition metal complex selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a phosphorescent complex of a tetrabenzoporphyrin, a chlorin, a porphyrin-ketone, an aza-porphyrin and a long-decay luminescent complex of iridium(III) or osmium(II).
  • an oxygen sensitive photoluminescent transition metal complex selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a
  • the polymeric matrix component is selected from the group consisting of silicone, polystrene, polycarbonate, and polysulfone.
  • an article of commerce comprising a plurality of probes as described above retained as a commingled supply of probes within a container from which the probes may be individually and discretely dispensed.
  • the probes within the container are sanitized probes.
  • the probes within the container are sterilized probes.
  • a method for measuring concentration of a target-analyte within an enclosed space comprising the steps of:
  • the space is hermetically enclosed, and the method further comprises the step of placing a liquid test sample into the space prior to hermetically enclosing the space.
  • the space is enclosed within a receptacle, (ii) a single probe is placed within the space, and (ii) the probe is contactlessly interrogated through the receptacle.
  • the method further comprises the step of placing a liquid test sample into the space prior to enclosing the space, (iii) the placed probes each have a density greater than the liquid test sample placed into the space, whereby the placed probes sink to the bottom of the receptacle, and (iv) the placed probes are contactlessly interrogated through the bottom of the receptacle.
  • a method for measuring concentration of a target-analyte within an enclosed space comprising the steps of:
  • a method for measuring concentration of a target-analyte within the chamber of a plurality of receptacles comprising the steps of:
  • a method for monitoring changes in target-analyte concentration within an enclosed space comprising the steps of:
  • the space is hermetically enclosed, and the method further comprises the step of placing a liquid test sample into the space prior to hermetically enclosing the space.
  • the space is enclosed within a receptacle, (ii) a single probe is placed within the space, and (ii) the probe is contactlessly interrogated through the receptacle.
  • the method is applied to achieve at least one of (i) a measurement of chemical activity of the test sample, (ii) a measurement of biological activity of the test sample, (iii) a presence/absence determination of a threshold concentration of aerobic microorganisms in the test sample, and (iv) an enumeration of aerobic microorganisms in the test sample at the time the test sample is placed in the space.
  • a method for monitoring changes in target-analyte concentration within an enclosed space comprising the steps of:
  • a method for measuring concentration of a target-analyte of interest within an enclosed space wherein the target-analyte of interest is selectable from and selectively transitional amongst a plurality of different target-analytes without accessing the space once enclosed comprising the steps of:
  • a method for measuring concentration of at least two different target-analytes within an enclosed space comprising the steps of:
  • a method for monitoring changes in concentration of at least two different target-analytes within an enclosed space comprising the steps of:
  • a method of preparing the probe according to the invention which includes at least the steps of:
  • the coating cocktail further includes a polymer operable for forming a target-analyte permeable polymer matrix when dried.
  • the scaffold particle is soaked with the cocktail whereby the cocktail penetrates into and coats the pores in the scaffold particle, and the method further includes separating the coated scaffold particle from excess cocktail prior to drying.
  • target-analyte refers to a chemical substance, typically O 2 , CO 2 or pH, capable of proportionally altering an optical property of an optically-active material containing a photoluminescent dye.
  • contactless interrogation means interrogation without tangible physical contact with the interrogated device, whereby interrogation can occur through an intervening barrier.
  • the term "interrogation light” means electromagnetic radiation having a wavelength between 400 and 900 nm.
  • Luminescence encompasses both fluorescence and phosphorescence. Electromagnetic radiation in the ultraviolet or visible region is used to excite molecules to higher electronic energy levels. The excited molecules lose their excess energy by one of several methods. One of those methods is fluorescence. Fluorescence refers to the radiative transition of electrons from the first excited singlet state to the singlet ground state (Si .to S 0 ). The lifetime of fluorescence is relatively short, approximately 10 -9 to 10 -7 seconds.
  • the triplet state so produced may return to the ground state by a radiative process known as phosphorescence.
  • Phosphorescence is the radiative relaxation of an electron from the lowest excited triplet state to the singlet ground state (T 1 to S 0 ). Because the transition that leads to phosphorescence involves a change in spin multiplicity, it has a low probability and hence a relatively long lifetime of 10 -4 to 10 seconds. Fluorescent and phosphorescent intensity and lifetime are known to change in a defined fashion relative to changes in the partial pressure of a target-analyte capable of quenching the photoluminescent molecules. Hence, the partial pressure of a target-analyte in fluid communication with a photoluminescent material can be determined by measuring photoluminescence intensity and/or lifetime.
  • a first aspect of the invention are probes 10 capable of reporting the partial pressure, and thereby the concentration, of a target-analyte A (P A ).
  • the probes 10 are inexpensive, discrete, self-contained particles, which are remotely interrogatable by optical means and autonomously positionable, thereby permitting the probes 10 to be used for a wide variety of purposes and in combination with a wide variety of assay vessels to quickly, easily and reliably measure and monitor changes in analyte concentration in an environment.
  • the probes 10 are particularly well suited for measuring and monitoring changes in target-analyte concentration in an enclosed environment in a non-invasive and non-destructive manner.
  • the probes 10 are sensitive to a target-analyte A, such as O 2 , CO 2 , CO or H + .
  • a target-analyte A such as O 2 , CO 2 , CO or H + .
  • O 2 the target-analyte A since O 2 -sensitive probes are the most commonly used types of optically active probes.
  • the probes 10 each comprise a suitably sized porous scaffold particle 20 coated with a target-analyte A sensitive coating 30.
  • the porous scaffold particle 20 is preferably structurally stable, compatible with the solvent based target-analyte sensitive coating 30 during the coating process, and the dry coating 30, inert when used in accordance with its intended use, and exhibits excellent light scattering properties at the excitation and emission wavelengths for the target-analyte A sensitive coating 30.
  • porous scaffold particle 20 includes specifically, but not exclusively, glass, and polymers such as polyethylene, polypropylene, polytetrafluoroethylene, polystryrene, polycarbonate, polysulfone, polyvinyl chloride, crosslinked poly(styrene-divinylbenzene) and other similar co-polymers. Based upon its superior structural stability, coating compatability, and density, the preferred material is glass.
  • the scaffold particle 20 is preferably constructed from a material which is translucent to interrogation light.
  • the scaffold particle 20 is preferably a non-metalic, most preferably a nonferrous material, due to weight, cost and inability to provide sufficient porosity.
  • the scaffold particles 20 are preferably dry, homogeneous and non-aggregating. They may be in the form of beads, fibers, filaments, fines, pellets, powder, prills and the like.
  • the scaffold particles 20 are preferably selected so that the resultant particulate probe 10 has a density of greater than 1.2 g/cm 3 , most preferably a density of between 1.5 and 5 g/cm 3 so that the probe 10, when introduced into the chamber 59 of an assay vessel 50 through the open top 50a of the vessel 50 will remain at or sink to the bottom 50b of the vessel 50 when combined with common test sample materials S, thereby facilitating location and interrogation of the probe 10 within the assay vessel 50.
  • the target-analyte sensitive coating 30 is preferrably includes a target-analyte-sensitive photoluminescent dye 31 embedded with a target-analyte A permeable polymer matrix 32.
  • Preferred photoluminescent indicator dyes 31 are long-decay fluorescent or phosphorescent indicator dyes.
  • a nonexhaustive list of suitable P O2 sensitive photoluminescent indicator dyes 31 includes specifically, but not exclusively, ruthenium(II)-bipyridyl and ruthenium(II)-diphenylphenanothroline complexes, porphyrin-ketones such as platinum(II)-octaethylporphine-ketone, platinum(II)-porphyrin such as platinum(II)-tetrakis(pentafluorophenyl)porphine, palladium(II)-porphyrin such as palladium(II)-tetrakis(pentafluorophenyl)porphine, phosphorescent metallocomplexes of tetrabenzoporphyrins, chlorins, azaporphyrins, and long-decay luminescent complexes of iridium(III) or osmium(II).
  • the target-analyte sensitive photoluminescent dye 31 is compounded with and embedded within a suitable target-analyte permeable polymer matrix 32.
  • a suitable polymeric matrix 32 based upon the target-analyte A of interest, the selected dye 31 and the intended use of the probe 10.
  • suitable polymers for use as the oxygen-permeable polymer matrix 32 includes specifically, but not exclusively, polystryrene, polycarbonate, polysulfone, polyvinyl chloride and some co-polymers.
  • the optically active particulate probe 10 preferably has at least one of a volume between 0.5 and 500 mm 3 , preferably 5 to 100 mm 3 , and a largest dimension of between 2 and 20 mm, preferably 3 to 10 mm. Probes 10 with a volume smaller than 0.5 mm 3 and/or a largest dimension of less than 2 mm are difficult to handle and accurately dispense, while probes 10 with a volume greater than 500 mm 3 and/or a largest dimension of greater than 20 mm are too large for use in many common testing receptacles 50, such as many traditional assay vessels, and unnecessarily increases the cost of each probe 10.
  • the optically active particulate probe 10 can be manufactured by any suitable technique. It is generally advantageous for the scaffold particle 20 to have a uniform size.
  • the particle 20 may have a geometrical (e.g. , planar, rectangular, spherical, oval, etc) or irregular shape and may have a rough or smooth exterior surface.
  • One technique is to dissolve or suspend the indicator dye 31, preferably with target-analyte permeable polymer 32, in a suitable organic solvent such as ethylacetate, immersing the porous scaffold particles 20 of the desired type, size and shape in the solution to coat the particles 20, including the pores 29, with dye 31, removing the coated particles 20, and allowing the coated particles 20 to dry.
  • the solution may be sprayed onto the particles 20.
  • the concentration of indicator dye 21 in the organic solvent should be in the range of 0.01 to 5% w/w.
  • the concentration of the polymer 32 in the organic solvent should be in the range of 0.1 to 20% w/w, with the ratio of indicator dye 31 to polymer 32 in the range of 1:50 to 1:5,000 w/w.
  • the probes 10 can be supplied as an article of commerce comprising a plurality of the probes 10, (e.g ., 10 to 1,000 probes or more) retained as a commingled supply 100 of the probes 10 within a container 40 from which the probes 10 may be individually and discretely dispensed.
  • each probe 10 A1 and 10 A2 may be sorted, as shown in Figure 5 , or collated as shown in Figure 6 .
  • the particulate probes 10 may be sanitized or sterilized before or after being deposited into the container 40 by any suitable means, such as heat, gamma irradiation or ethylene oxide, on order to avoid microbial contamination of a sample S undergoing microbial testing with the probes 10.
  • the probe 10 can be used to quickly, easily, accurately and reliably measure the concentration of a target-analyte A in an environment (e.g ., the sealed chamber 59 of an assay vessel 50 or the sealed chamber (not shown) of a package (not shown) containing a product (not shown) susceptible to spoilage or deterioration).
  • the probe 10 can be interrogated in the same manner as typical target-analyte A sensitive photoluminescent probes are interrogated.
  • the probe 10 is used to measure the concentration of a target-analyte A in an environment by (A) placing the probe 10 into fluid communication with the environment to be monitored (e.g ., within the sealed chamber 59 of an assay vessel 50 containing a test sample S ) at a location where radiation at the excitation and emission wavelengths of the indicator dye 31 can be transmitted to and received from the probe 10 with minimal interference and without opening or otherwise breaching the integrity of the environment ( e.g. , without opening the assay vessel 50 ), (B) interrogating the probe 10 with an interrogation device (not shown), and (C) converting the measured emissions to a target-analyte A concentration within the environment based upon a known conversion algorithm or look-up table.
  • A placing the probe 10 into fluid communication with the environment to be monitored (e.g ., within the sealed chamber 59 of an assay vessel 50 containing a test sample S ) at a location where radiation at the excitation and emission wavelengths of the indicator dye 31 can be transmitted to and
  • the radiation emitted by the excited probe 10 can be measured in terms of photoluminescence intensity, intensity ratio and/or lifetime (rate of decay, phase shift or anisotropy), with measurement of lifetime generally preferred as a more accurate and reliable measurement technique when seeking to establish the extent to which the indicator dye 31 has been quenched by target-analyte A.
  • a preferred method of measuring the concentration of a target-analyte A within an enclosed space 59 employing a probe 10 includes the steps of (A) obtaining a supply 100 of the target-analyte sensitive probes 10, (B) placing a known number of probes 10 from the supply 100 of probes 10 within a space 59 to form a sensor 200 comprised of at least one probe 10, (C) enclosing the space 59, and (D) ascertaining target-analyte A concentration within the enclosed space 59 by: (i) exposing the sensor 200 to excitation radiation to create an excited sensor 200, (ii) measuring radiation emitted by the excited sensor 200, and (iii) converting the measured emission to a target-analyte A concentration based upon a known conversion algorithm.
  • Probes 10 are uniquely suited for measuring concentration of a target-analyte A within the chamber 59 of a plurality of dissimilar assay vessels 50.
  • the method includes the steps of (A) obtaining a supply 100 of probes 10 retained within a container 40, (B) dispensing a first known number of probes 10 from the container 40, constituting a first fraction of the total number of commingled probes 10, into a chamber 59 defined by a first assay vessel 50 1 to form a first sensor 200 1 comprised of at least one probe 10, (C) dispensing a second known number of probes 10 from the same container 40, constituting a second fraction of the total number of commingled probes 10, into the chamber 59 of a second assay vessel 50 2 to form a second sensor 200 2 comprised of at least one probe 10, wherein the second assay vessel 50 2 is different than and dissimilar to the first r assay vessel 50 1 , (D) enclosing the chamber 59 defined by the
  • the probe 10 can also be used to quickly, easily, accurately and reliably monitor changes in target-analyte A concentration in an environment by (i) placing the probe 10 into fluid communication with the environment to be monitored at a location where radiation at the excitation and emission wavelengths of the indicator dye 31 can be transmitted to and received from the probe 10 with minimal interference and without opening or otherwise breaching the integrity of the environment, (B) ascertaining the target-analyte A concentration within the environment over time by (i) repeatedly exposing the probe 10 to excitation radiation over time, (ii) measuring radiation emitted by the excited probe 10 after at least some of the exposures, (iii) measuring passage of time during the repeated excitation exposures and emission measurements, and (iv) converting at least some of the measured emissions to a target-analyte A concentration based upon a known conversion algorithm, and (C) reporting at least one of (i) at least two ascertained target-analyte A concentrations and the time interval between those reported concentrations, and (ii) a
  • a preferred method for monitoring changes in target-analyte A concentration within an enclosed space 59 employing a probe 10 includes the steps of (A) obtaining a supply 100 of the probes 10, (B) placing a known number of probes 10 from the supply 100 of probes 10 within a space 59 to form a sensor 200 comprised of at least one probe 10, (C) enclosing the space 59, (D) ascertaining target-analyte A concentration within the enclosed space 59 over time by: (i) taking at least two emission measurements over time, each measurement comprising the steps of: (1) exposing the sensor 200 to excitation radiation to create an excited sensor 200, and (2) measuring radiation emitted by the excited sensor 200, (ii) measuring passage of time between at least two of the emission measurements to determine a time interval between identified emission measurements, and (iii) converting at least the identified emission measurements to a target-analyte A concentration based upon a known conversion algorithm, and (E) reporting at least one of (i
  • Probes 10 are also uniquely suited for measuring concentration of a target-analyte A of interest within an enclosed space 59 employing different probes 10 sensitive to different target-analytes A (e.g ., probe 10 A1 sensitive to target-analyte A1 and probe 10 A2 sensitive to target-analyte A2 ), wherein the target-analyte A of interest is selectable from and selectively transitional amongst a plurality of different target-analytes A without accessing the space 59 once enclosed.
  • different probes 10 sensitive to different target-analytes A e.g ., probe 10 A1 sensitive to target-analyte A1 and probe 10 A2 sensitive to target-analyte A2
  • the target-analyte A of interest is selectable from and selectively transitional amongst a plurality of different target-analytes A without accessing the space 59 once enclosed.
  • the method includes the steps of (A) obtaining a supply 100 of probes 10 wherein the supply includes probes 10 that are sensitive to different target-analytes A (e.g ., a supply 100 1 of probes 10 A1 sensitive to target-analyte A1 and a supply 100 2 of probes 10 A2 sensitive to target-analyte A2 ) and are uniquely interrogatable relative to one another, (B) placing at least two of the obtained probes 10 sensitive to different target-analytes A within a space 59, to form a sensor 200 sensitive to at least two different target-analytes A (e.
  • target-analyte A1 and target-analyte A2 g., target-analyte A1 and target-analyte A2
  • C enclosing the space 59
  • D ascertaining concentration of a target-analyte A of interest within the enclosed space, selected from the at least two different target-analytes A to which the at least two placed probes 10 are sensitive (e.g ., probe 10 A1 sensitive to target-analyte A1 and probe 10 A2 sensitive to target-analyte A2 ), by: (i) exposing the sensor 200 to excitation radiation effective for exciting the probe 10 sensitive to the target-analyte A of interest ( e.g ., probe 10 A1 sensitive to target-analyte A1 ), (ii) measuring radiation emitted by the excited probe 10 sensitive to the target-analyte A of interest ( e.g ., probe 10 A1 sensitive to target-analyte A1
  • Probes 10 are also uniquely suited for measuring the concentration of at least two different target-analytes A (e.g ., target-analyte A1 and target-analyte A2 ) within an enclosed space 59 employing different target-analyte sensitive probes 10 (e.g. , probe 10 A1 sensitive to target-analyte A1 and probe 10 A2 sensitive to target-analyte A2 ).
  • the method includes the steps of (A) obtaining a first supply 100 1 of target-analyte sensitive probes 10 A1 which are sensitive to a first target-analyte A1, (B) obtaining a second supply 100 2 of target-analyte sensitive probes 10 A2 which are sensitive to a second target-analyte A2 which is different from the first target-analyte A1 , and wherein the probes 10 A1 sensitive to a first target-analyte A1 and the probes 10 A2 sensitive to a second target-analyte A2 are uniquely interrogatable relative to one another, (C) placing at least one probe 10 A1 from the first supply of probes 100 1 and at least one probe 10 A2 from the second supply of probes 100 2 within a space 50, to form a sensor 200 sensitive to both first A1 and second A2 target-analytes, (D) enclosing the space 59, (E) ascertaining concentration of the first target-analy
  • Probes 10 are suited for simultaneously monitoring changes in the concentration of different target-analytes A of interest (e.g ., target-analyte A1 and target-analyte A2 ) within an enclosed space 59.
  • the method includes the steps of (A) obtaining a first supply 100 1 of target-analyte sensitive probes 10 A1 which are sensitive to a first target-analyte A1, (B) obtaining a second supply 100 2 of target-analyte sensitive probes 10 A2 which are sensitive to a second target-analyte A2 which is different from the first target-analyte A1 , and wherein the probes 10 A1 sensitive to a first target-analyte A1 and the probes 10 A2 sensitive to a second target-analyte A2 are uniquely interrogatable relative to one another, (C) placing at least one probe 10 A1 from the first supply of probes 100 1 and at least one probe 10 A2 from the second supply of
  • the phosphorescent oxygen-sensitive dye platinum(II) benzoporphyrin was dissolved in a 5% solution of polystyrene in ethylacetate at a concentration of 1 mg platinum(II) benzoporphyrin / ml of solution to form a coating cocktail. 100g of 4 mm diameter porous glass beads were soaked in the cocktail, separated on a mesh screen, dried on aluminum foil at room temperature for 2 hours, and placed into a container for future use.
  • the probe produced according to Example 1 is transferred aseptically into a 15 ml sterile plastic vial with a screw cap. An aliquot of food or a medical sample, combined with a medium for supporting growth of microorganisms, is added aseptically to the vial along with the probe. The vial is capped and immediately thereafter the probe within the vial is externally interrogated with an Optech TM platinum external detector available from Mocon, Inc. to obtain an initial t 0 photoluminescence lifetime signal. The vial with its contents is incubated in an incubator at 30°C for 24 hours, at which time the probe within the vial is again interrogated with the Optech TM platinum detector and an incubated ti photoluminescence lifetime signal measured.
  • any increase in the signal after incubation indicates a proportional decrease in O 2 concentration within the vial as a result of the metabolic consumption of O 2 within the vial by microorganism introduced into the vial by the sample aliquot.
  • a significant increase denotes that the sample aliquot as introduced into the vial was non-sterile, while a lack of any increase or a small increase denotes that the sample aliquot as introduced into the vial was sterile.

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  • General Health & Medical Sciences (AREA)
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  • Pathology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Optics & Photonics (AREA)
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  • Plasma & Fusion (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Claims (13)

  1. Sonde (10) sensible à l'analyte cible, discrète et déployable de manière flexible, adaptée pour être distribuée individuellement et discrètement, comprenant une particule d'échafaudage poreuse (20) revêtue d'un matériau optiquement actif, sensible à l'analyte cible (30), dans laquelle la particule d'échafaudage (20) est une bille et présente au moins l'un(e) parmi (i) un volume allant de 0,5 à 500 mm3, et ii) une dimension la plus grande allant de 2 à 20 mm.
  2. Sonde (10) selon la revendication 1, dans laquelle la particule d'échafaudage (20) présente une dimension la plus grande allant de 3 à 10 mm.
  3. Sonde (10) selon la revendication 1, la sonde (10) présentant une densité supérieure à 1,2 g/cm3.
  4. Sonde (10) selon la revendication 1, dans laquelle le matériau de particule d'échafaudage (20) est constitué de verre poreux.
  5. Sonde (10) selon la revendication 1, dans laquelle le matériau sensible à l'analyte cible (30) est un matériau photoluminescent, où le matériau photoluminescent comporte au moins un colorant indicateur fluorescent ou phosphorescent ayant une caractéristique optique réactive qui change en réponse aux variations de concentration ou de pression partielle de l'analyte cible auquel le colorant est exposé.
  6. Sonde (10) selon la revendication 1, dans laquelle (i) la caractéristique optique réactive est au moins l'une parmi la durée de vie de la photoluminescence et l'intensité de la photoluminescence, et (ii) le colorant indicateur est sensible à la pression partielle de l'oxygène.
  7. Sonde (10) selon la revendication 1, dans laquelle le revêtement comprend un colorant indicateur sensible à l'analyte cible incorporé dans une matrice polymère perméable à l'analyte cible (32), où le colorant indicateur sensible à l'analyte cible est un complexe de métal de transition photoluminescent sensible à l'oxygène choisi dans le groupe constitué par une bipyridine de ruthénium, une diphénylphénantroline de ruthénium, une porphyrine de platine, une porphyrine de palladium, un complexe phosphorescent d'une tétrabenzoporphyrine, une chlorine, une porphyrine-cétone, une aza-porphyrine et un complexe luminescent à longue durée de vie d'iridium(III) ou d'osmium(II).
  8. Article de commerce, comprenant une pluralité de sondes (10) selon la revendication 1 conservées sous forme de réserve mélangée de sondes (100) au sein d'un conteneur (40) à partir duquel les sondes (10) peuvent être distribuées individuellement et discrètement.
  9. Article de commerce selon la revendication 8, dans lequel les sondes au sein du conteneur (40) sont des sondes (10) aseptisées ou stérilisées.
  10. Méthode de mesure de la concentration en un analyte cible au sein d'un espace clos, comprenant les étapes
    (a) d'obtention d'une réserve de sondes sensibles à l'analyte cible (10) selon la revendication 1, ou d'obtention d'un article de commerce selon la revendication 8,
    (b) de placement d'un nombre connu de sondes (10) provenant de la réserve de sondes (100) selon la revendication 1 au sein d'un espace afin de former un capteur (200) composé d'au moins une sonde (10), ou de placement d'un nombre connu de sondes (10) provenant du conteneur (40) de l'article de commerce selon la revendication 8, constituant une fraction du nombre total de sondes mélangées (10), dans un espace afin de former un capteur (200) composé d'au moins une sonde (10),
    (c) de clôture de l'espace, et
    (d) de détermination de la concentration en analyte cible dans l'espace clos, en
    (i) exposant le capteur (200) à un rayonnement d'excitation afin de créer un capteur (200) excité,
    (ii) mesurant le rayonnement émis par le capteur (200) excité, et
    (iii) convertissant l'émission mesurée en une concentration en analyte cible sur la base d'un algorithme de conversion connu.
  11. Méthode de mesure de la concentration en un analyte cible selon la revendication 10, dans laquelle l'espace clos se trouve au sein de la chambre (59) d'une pluralité de récipients, où l'étape (a) comprend l'obtention d'un article de commerce selon la revendication 8, et où l'étape (b) comprend
    la distribution d'un premier nombre connu de sondes (10) provenant du conteneur (40), constituant une première fraction du nombre total de sondes (10) mélangées, dans une chambre (59) définie par un premier récipient afin de former un premier capteur (200) constitué d'au moins une sonde (10), et la distribution d'un deuxième nombre connu de sondes (10) provenant du même conteneur (40), constituant une deuxième fraction du nombre total de sondes mélangées, dans la chambre d'un deuxième récipient afin de former un deuxième capteur (200) constitué d'au moins une sonde (10), où le deuxième récipient est différent et dissemblable du premier récipient,
    où l'étape (c) comprend la clôture de la chambre (59) définie par le premier récipient, et la clôture de la chambre définie par le deuxième récipient,
    où l'étape (d) comprend la détermination de la concentration en analyte cible dans la chambre close du premier récipient, en
    (i) exposant le premier capteur (200) à un rayonnement d'excitation afin de créer un premier capteur (200) excité,
    (ii) mesurant le rayonnement émis par le premier capteur (200) excité, et
    (iii) convertissant l'émission mesurée en une concentration en analyte cible sur la base d'un algorithme de conversion connu, et
    la détermination de la concentration en analyte cible au sein de la chambre close du deuxième récipient, en
    (i) exposant le deuxième capteur (200) à un rayonnement d'excitation afin de créer un deuxième capteur (200) excité,
    (ii) mesurant le rayonnement émis par le deuxième capteur (200) excité, et
    (iii) convertissant l'émission mesurée en une concentration en analyte cible sur la base d'un algorithme de conversion connu.
  12. Méthode de suivi des variations de la concentration en analyte cible au sein d'un espace clos, selon la revendication 10,
    dans laquelle l'étape (d) comprend la détermination de la concentration en analyte cible au sein de l'espace clos au cours du temps, en
    (i) prenant au moins deux mesures d'émission au cours du temps, chaque mesure comprenant les étapes :
    (1) d'exposition du capteur (200) à un rayonnement d'excitation afin de créer un capteur (200) excité, et
    (2) de mesure du rayonnement émis par le capteur (200) excité,
    (ii) mesurant le passage du temps entre au moins deux parmi les mesures d'émission afin de déterminer un intervalle de temps entre les mesures d'émission identifiées, et
    (iii) convertissant au moins les mesures d'émission identifiées en une concentration en analyte cible sur la base d'un algorithme de conversion connu, et
    la méthode comprenant en outre l'étape (e) consistant à rapporter au moins l'un(e) parmi (i) au moins les deux concentrations en analyte cible déterminées et l'intervalle de temps entre ces concentrations rapportées, et (ii) un taux de variation de la concentration en analyte cible au sein de l'espace clos, calculé à partir des données obtenues à l'étape (d).
  13. Méthode selon la revendication 10, dans laquelle l'analyte cible d'intérêt peut être sélectionné, et sélectivement transitionnel, parmi une pluralité d'analytes cibles différents, sans accéder à l'espace une fois qu'il est clos,
    dans laquelle l'étape (a) comprend l'obtention d'une réserve de sondes sensibles à l'analyte cible (10) selon la revendication 1, où la réserve comporte des sondes (10) qui sont sensibles à différents analytes cibles et interrogeables de manière unique les unes par rapport aux autres,
    où l'étape (b) comprend le placement d'au moins deux parmi les sondes (10) obtenues et sensibles à différents analytes cibles au sein d'un espace, afin de former un capteur (200) sensible à au moins deux analytes cibles différents,
    où l'étape (d) comprend la détermination de la concentration en un analyte cible d'intérêt au sein de l'espace clos, choisi parmi les au moins deux analytes cibles différents auxquels les au moins deux sondes (10) placées sont sensibles, en
    (i) exposant le capteur (200) à un rayonnement d'excitation efficace afin d'exciter la sonde (10) sensible à l'analyte cible d'intérêt,
    (ii) mesurant le rayonnement émis par la sonde (10) excitée et sensible à l'analyte cible d'intérêt, et
    (iii) convertissant l'émission mesurée en une concentration en analyte cible d'intérêt sur la base d'un algorithme de conversion connu.
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